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Glutamate- Central role in amino acid metabolism
Answer- Glutamate occupies a central place in amino acid metabolism. Basically it acts as a collector of amino group of the amino acids. Free ammonia is toxic to the body especially to brain cells, it is transported in the bound form to liver where it is finally detoxified forming urea.
Amino acids not needed as building blocks are degraded to specific compounds. The major site of amino acid degradation in mammals is the liver. The amino group must be removed, in as much as there are no nitrogenous compounds in energy-transduction pathways. Amino group can be transferred (Transamination) or it can be removed in the form of ammonia (Deamination). The α-keto acids that result from amino acids are metabolized so that the carbon skeletons can enter the metabolic main stream as precursors to glucose or citric acid cycle intermediates.
The formation and fate of glutamate and significance of these processes related to metabolism of amino acids can be explained as follows-
Sources of Glutamate include-
1) Transamination of amino acids
2) Hydrolysis of Glutamine
3) Metabolic product of amino acids
Fate of Glutamate
1) Oxidative deamination to from Alpha keto glutarate
2) Amination to form Glutamine
3) Decarboxylation to form GABA (Gamma amino butyric acid)
4) Formation of N-Acetyl Glutamate
All processes except GABA formation are involved in the catabolism of amino acids and transport of amino group or ammonia.
1) Transamination and role of Glutamate
a) General reactions
Aminotransferases catalyze the transfer of an α-amino group from an α-amino acid to an α-keto acid. These enzymes, also called transaminases, generally funnel α-amino groups from a variety of amino acids to α-keto-glutarate for conversion into NH4 +(Figure-1)
Figure-1- showing the transfer of alpha amino group to an-α keto acid catalyzed by amino transferase
The α -amino group of many amino acids is transferred to α -ketoglutarate to form glutamate, which is then oxidatively deaminated to yield ammonium ion (NH4) (Figure-2)
Figure-2- showing the general role of glutamate in the transfer of amino group of amino acid that can be subsequently removed as ammonium ion.
All the amino acids except lysine, threonine, proline, and hydroxyproline participate in transamination. Transamination is readily reversible, and aminotransferases also function in amino acid biosynthesis.
b) Special reactions
1) Aspartate aminotransferase, one of the most important of these enzymes, catalyzes the transfer of the amino group of aspartate to α-ketoglutarate.
2) Alanine aminotransferase catalyzes the transfer of the amino group of alanine to α -ketoglutarate.
2) Deamination of glutamate- The nitrogen atom that is transferred to α-ketoglutarate in the transamination reaction (forming Glutamate) is converted into free ammonium ion by oxidative deamination. This reaction is catalyzed by glutamate dehydrogenase. This enzyme is unusual in being able to utilize either NAD+ or NADP+, at least in some species. The reaction proceeds by dehydrogenation of the C-N bond, followed by hydrolysis of the resulting Schiff base.
Figure-3- Showing the oxidative deamination of Glutamate to from α- Keto glutarate. Glutamate carries the amino group of amino acids from peripheral tissue to liver to be released as ammonium ions .
The equilibrium for this reaction favors glutamate; the reaction is driven by the consumption of ammonia. Glutamate dehydrogenase is located in mitochondria, as are some of the other enzymes required for the production of urea. This compartmentalization sequesters free ammonia, which is toxic.
The sum of the reactions catalyzed by aminotransferases and glutamate dehydrogenase is-
In most terrestrial vertebrates, NH4 + is converted into urea, which is excreted (Figure-4)
Figure-4-Showing the process of transdeamination and the role of glutamate
Role of Glutamate and Glutamate dehydrogenase- In majority of the transamination reactions alpha keto glutarate is the acceptor keto acid forming Glutamate, that is oxidatively deaminated in the liver by Glutamate dehydrogenase to form alpha keto glutarate and ammonia. Conversion of α-amino nitrogen to ammonia by the concerted action of glutamate aminotransferase and GDH is often termed “transdeamination.” Thus Transamination and deamination are coupled processes though they occur at distant places and in these two processes Glutamate occupies the central place.
Regulation of Glutamate dehydrogenase– The activity of glutamate dehydrogenase is allosterically regulated. The enzyme consists of six identical subunits. Guanosine triphosphate (GTP) and adenosine triphosphate (ATP) are allosteric inhibitors, whereas guanosine diphosphate (GDP) and adenosine diphosphate (ADP) are allosteric activators. Hence, a lowering of the energy charge (more of ADP and GDP) accelerates the oxidation of amino acids favoring formation of alpha keto glutarate that can be channeled towards TCA cycle for complete oxidation to provide energy.
3) Glucose alanine cycle and the role of Glutamate- The transport of amino group of amino acids also takes place in the form of Alanine.
Nitrogen is transported from muscle to the liver in two principal transport forms. Glutamate is formed by transamination reactions, but the nitrogen is then transferred to pyruvate to form alanine, which is released into the blood. The liver takes up the alanine and converts it back into pyruvate by transamination. The pyruvate can be used for gluconeogenesis and the amino group eventually appears as urea. This transport is referred to as the alanine cycle. It is reminiscent of the Cori cycle and again illustrates the ability of the muscle to shift some of its metabolic burden to the liver (Figure-5)
Figure-5- The Glucose- Alanine Cycle- Glutamate in muscle is transaminated to alanine, which is released into the blood stream. In the liver, alanine is taken up and converted into pyruvate for subsequent metabolism.
) Glutamate and Glutamine relationship
Ammonia Nitrogen can also be transported as glutamine. This is the first line of defense in brain cells. Glutamine synthetase catalyzes the synthesis of glutamine from glutamate and NH4 + in an ATP-dependent reaction (Figure-6)
Figure-6- Showing the synthesis of glutamine form glutamate
The nitrogen of glutamine can be converted into urea in the liver.
Hydrolytic release of the amide nitrogen of glutamine as ammonia, catalyzed by glutaminase (Figure -7 )strongly favors glutamate formation. The concerted action of glutamine synthase and glutaminase thus catalyzes the interconversion of free ammonium ion and glutamine.
Figure-7- showing the hydrolysis of glutamine by glutaminase.
Renal glutaminase activity is associated with maintenance of acid base metabolism.
5) Glutamate as a metabolic product– Glutamate is produced directly from the metabolism of Proline, Arginine and Histidine, that can be oxidatively deaminated to form Alpha keto glutarate and ammonia. (Figure-8)
Figure-8- Showing the formation of glutamate from amino acids like Arginine, Histidine and Proline
6) Glutamate as an activator for urea formation– Glutamate in the form of N-Acetyl Glutamate acts as a positive allosteric modifier for Carbamoyl phosphate synthetase-1 , the first and the rate limiting enzyme of urea cycle. Carbamoyl phosphate synthase I, is active only in the presence of its allosteric activator N-acetylglutamate, which enhances the affinity of the synthase for ATP (Figure-9)
Figure-9- Showing the role of N-Acetyl Glutamate as a positive modifier for CPS-1
6) Formation of GABA- GABA, an inhibitory neurotransmitter is produced from the decarboxylation of glutamic acid by glutamate decarboxylase enzyme in the presence of B6-P (Figure-10)
Figure-10– showing the synthesis of GABA from glutamate.
Ammonia intoxication and role of glutamate- Excess of ammonia depletes glutamate and hence GABA level in brain, To compensate for glutamate, alpha keto glutarate is used , the decrease concentration of which subsequently depresses TCA and thus deprives brain cells of energy. Excess Glutamine is exchanged with Tryptophan , a precursor of Serotonin , resulting in hyper excitation. The symptoms of ammonia intoxication are all due to energy depletion and a state of hyperexcitation.
Thus to conclude, Glutamate represents the major transporter of amino group of amino acids and has a central role in both the catabolism of amino acids as well in the synthesis of non- essential amino acids( through Transamination reactions).
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